tbuckley/cabot-search huggingface dataset:
Twenty-Year Experience and Outcomes in a National Pediatric Pulmonary Hypertension Service
Authors: Andrew Constantine, Konstantinos Dimopoulos, Sheila G. Haworth, Vivek Muthurangu, Shahin Moledina
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Pediatric pulmonary hypertension is an important cause of childhood morbidity and mortality, but there are limited data on the range of associated diseases, contributions of different pulmonary hypertension subtypes, therapeutic strategies, and clinical outcomes in children. Objectives: To report the 20-year experience of a large UK National Pediatric Pulmonary Hypertension Service focusing on epidemiology and clinical outcomes. Methods: Consecutive patients presenting between 2001 and 2021 were included, and survival analysis was performed for incident patients. Measurements and Main Results: Of 1,353 patients assessed, a pulmonary hypertension diagnosis was made in 1,101 (81.4%) patients (51% female, median age, 2.6 [interquartile range, 0.8–8.2] years). The most common form was pulmonary arterial hypertension in 48%, followed by 32.3% with pulmonary hypertension due to lung disease. Multiple contributory causes of pulmonary hypertension were common, with 16.9% displaying features of more than one diagnostic group. The annual incidence of childhood pulmonary hypertension was 3.5 (95% confidence interval [CI], 3.3–3.8) per 1 million children, and the prevalence was 18.1 (95% CI, 15.8–20.4) per 1 million. The incidence was highest for pulmonary hypertension due to lung disease in infancy (15.0 [95% CI, 12.7–17.2] per 1 million per year). Overall, 82.4% patients received pulmonary arterial hypertension therapy, and escalation to triple therapy during follow-up was required in 13.1%. In 970 (88.1%) incident patients, transplant-free survival was 86.7% (95% CI, 84.5–89%) at 1 and 68.6% (95% CI, 64.7–72.6%) at 10 years. Pulmonary hypertension due to left heart disease had the lowest survival (hazard ratio, 2.0; 95% CI, 1.36–2.94; P < 0.001). Conclusions: Clinical phenotypes of pediatric pulmonary hypertension are heterogeneous and overlapping, with clinical phenotypes that evolve throughout childhood. Despite widespread use of pulmonary arterial hypertension therapy, the prognosis remains poor.
Incidence of chikungunya virus infections among Kenyan children with neurological disease, 2014–2018: A cohort study
Authors: Doris K. Nyamwaya, Mark Otiende, Lilian Mwango, Symon M. Kariuki, Berrick Otieno, Donwilliams O. Omuoyo, George Githinji, Barnes S. Kitsao, Henry K. Karanja, John N. Gitonga, Zaydah R. de Laurent, Alun Davies, Salim Mwarumba, Charles N. Agoti, Samuel M. Thumbi, Mainga M. Hamaluba, Charles R. Newton, Philip Bejon, George M. Warimwe
Journal: PLoS Medicine (2022)

Neurological complications due to chikungunya virus (CHIKV) infection have been described in different parts of the world, with children being disproportionately affected. However, the burden of CHIKV-associated neurological disease in Africa is currently unknown and given the lack of diagnostic facilities in routine care it is possible that CHIKV is an unrecognized etiology among children with encephalitis or other neurological illness.
Assessment of mortality and hospital admissions associated with confirmed infection with SARS-CoV-2 Alpha variant: a matched cohort and time-to-event analysis, England, October to December 2020
Authors: Gavin Dabrera, Hester Allen, Asad Zaidi, Joe Flannagan, Katherine Twohig, Simon Thelwall, Elizabeth Marchant, Nurin Abdul Aziz, Theresa Lamagni, Richard Myers, André Charlett, Fernando Capelastegui, Dimple Chudasama, Tom Clare, Flavien Coukan, Mary Sinnathamby, Neil Ferguson, Susan Hopkins, Meera Chand, Russell Hope, Meaghan Kall
Journal: Eurosurveillance (2022)

Background The emergence of the SARS-CoV-2 Alpha variant in England coincided with a rapid increase in the number of PCR-confirmed COVID-19 cases in areas where the variant was concentrated. Aim Our aim was to assess whether infection with Alpha was associated with more severe clinical outcomes than the wild type. Methods Laboratory-confirmed infections with genomically sequenced SARS-CoV-2 Alpha and wild type between October and December 2020 were linked to routine healthcare and surveillance datasets. We conducted two statistical analyses to compare the risk of hospital admission and death within 28 days of testing between Alpha and wild-type infections: a matched cohort study and an adjusted Cox proportional hazards model. We assessed differences in disease severity by comparing hospital admission and mortality, including length of hospitalisation and time to death. Results Of 63,609 COVID-19 cases sequenced in England between October and December 2020, 6,038 had the Alpha variant. In the matched cohort analysis, we matched 2,821 cases with Alpha to 2,821 to cases with wild type. In the time-to-event analysis, we observed a 34% increased risk in hospitalisation associated with Alpha compared with wild type, but no significant difference in the risk of mortality. Conclusion We found evidence of increased risk of hospitalisation after adjusting for key confounders, suggesting increased infection severity associated with the Alpha variant. Rapid assessments of the relative morbidity in terms of clinical outcomes and mortality associated with emerging SARS-CoV-2 variants compared with dominant variants are required to assess overall impact of SARS-CoV-2 mutations.
Lipoprotein(a) and its Significance in Cardiovascular Disease
Authors: Freddy Duarte Lau, Robert P. Giugliano
Journal: JAMA Cardiology (2022)

<h3>Importance</h3> Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol–like particle bound to apolipoprotein(a). This novel marker of cardiovascular disease acts through induction of vascular inflammation, atherogenesis, calcification, and thrombosis. While an absolute risk threshold remains to be universally accepted, an estimated 20% to 25% of the global population have Lp(a) levels of 50 mg/dL or higher, a level noted by the European Atherosclerosis Society to confer increased cardiovascular risk. <h3>Observations</h3> Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing therapies. The ineffectiveness of lifestyle modification, statins, and ezetimibe to lower Lp(a); the modest Lp(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors; the adverse effect profile and unclear cardiovascular benefit of pharmacotherapies such as niacin and mipomersen; and the impracticality of regular lipoprotein apheresis represent major challenges to currently available therapies. Nevertheless, emerging nucleic acid–based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects. Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials. <h3>Conclusions and Relevance</h3> Epidemiologic and genetic studies suggest a potentially causal association between elevated Lp(a) levels, atherosclerotic cardiovascular disease, and aortic valve stenosis. Emerging nucleic acid–based therapies have potent Lp(a)-lowering effects and appear safe; phase 3 trials will establish whether they improve cardiovascular outcomes.
Noncoding RNAs related to the hedgehog pathway in cancer: clinical implications and future perspectives
Authors: Jia Song, Yuexin Ge, Xiaoyu Sun, Qiutong Guan, Shiqiang Gong, Minjie Wei, Jumin Niu, Lin Zhao
Journal: Molecular Cancer (2022)

Abstract Cancer is a type of malignant affliction threatening human health worldwide; however, the molecular mechanism of cancer pathogenesis remains to be elusive. The oncogenic hedgehog (Hh) pathway is a highly evolutionarily conserved signaling pathway in which the hedgehog-Patched complex is internalized to cellular lysosomes for degradation, resulting in the release of Smoothened inhibition and producing downstream intracellular signals. Noncoding RNAs (ncRNAs) with diversified regulatory functions have the potency of controlling cellular processes. Compelling evidence reveals that Hh pathway, ncRNAs, or their crosstalk play complicated roles in the initiation, metastasis, apoptosis and drug resistance of cancer, allowing ncRNAs related to the Hh pathway to serve as clinical biomarkers for targeted cancer therapy. In this review, we attempt to depict the multiple patterns of ncRNAs in the progression of malignant tumors via interactions with the Hh crucial elements in order to better understand the complex regulatory mechanism, and focus on Hh associated ncRNA therapeutics aimed at boosting their application in the clinical setting.
Candelabrum cells are ubiquitous cerebellar cortex interneurons with specialized circuit properties
Authors: Tomas Osorno, Stephanie Rudolph, Tri Nguyen, Velina Kozareva, Naeem M. Nadaf, Aliya Norton, Evan Z. Macosko, Wei-Chung Allen Lee, Wade G. Regehr
Journal: Nature Neuroscience (2022)
Obituary in memory of Giovanni Pajno
Authors: Stefania Arasi, Lucia Caminiti, Giuseppe Crisafulli, Francesco Gugliemo, Antonella Muraro, Giovanni Passalacqua, Giovanni Corsello, Ilenia Panasiti, Fernanda Chiera, Andrea Barbalace, Mübeccel Akdis, Cezmi A. Akdis
Journal: Allergy (2022)

The authors have no conflict of interest in relation to this work. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Abstract A003: Genome evolution of a transmissible cancer in the soft-shell clam (<i>Mya arenaria</i>)
Authors: Samuel F.M. Hart, Rachael M. Giersch, Marisa A. Yonemitsu, Brian Beal, Stephen P. Goff, Michael J. Metzger
Journal: Cancer Research (2022)

Abstract A small number of transmissible cancer lineages exist in which cancer cells metastasize repeatedly to new hosts and live past the death of their original hosts. Transmissible cancers have been observed in the dog, Tasmanian devil, and most recently in numerous bivalves species, including one lineage that has spread through the soft-shell clam (Mya arenaria) population along the east coast of North America. We assembled a highly contiguous 1.2 Gb soft-shell clam reference genome and characterized the genome evolution of this transmissible cancer lineage. Our analyses confirm that all cancer samples descended from a single founder clam, but cluster in two geographically separated sub-lineages. In both sub-lineages, we observe high somatic mutation density, widespread copy number gain, structural rearrangement and transposable element activity, all indicative an unstable cancer genome. We also discovered a novel mutational signature generating mutations at a stable rate, predicting the cancer to be 344 to 877 years old and indicating it spread undetected long before it was first observed in the 1970s. Citation Format: Samuel F.M. Hart, Rachael M. Giersch, Marisa A. Yonemitsu, Brian Beal, Stephen P. Goff, Michael J. Metzger. Genome evolution of a transmissible cancer in the soft-shell clam (Mya arenaria) [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A003.
Evaluation of the Trajectory of Depression Severity With Ketamine and Esketamine Treatment in a Clinical Setting
Authors: Sina Nikayin, Taeho Greg Rhee, Maria Elena Cunningham, Christina A. de Fontnouvelle, Robert B. Ostroff, Gerard Sanacora, Samuel T. Wilkinson
Journal: JAMA Psychiatry (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
The Quest to Eradicate HPV-Related Oropharyngeal Carcinoma: An Opportunity Not to Miss
Authors: Chloe S Lalonde, Yong Teng, Barbara A Burtness, Robert L Ferris, Rafi Ahmed, Nabil F Saba
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Oropharyngeal squamous cell carcinoma (OPSCC) accounts for more than half of all head and neck cancers. Since the 1970s, OPSCC has shifted from an environmentally triggered to virally mediated disease due to a sharp rise in human papillomavirus (HPV)–related squamous cell carcinoma. Although a highly effective prophylactic vaccine is available, its current implementation is far below national targets, and OPSCC incidence is predicted to further increase by 2045. However, we believe that with prompt action now, we can not only defy these predictions but also effectively eradicate HPV-related OPSCC in these next 20 years. We herein provide an overview of the necessary elements to eliminate this disease: improved primary vaccine uptake, a 1-time universal vaccination effort, and implementation of novel therapeutics that have potential to cure existing disease.
Do Female <i>BRCA2</i> Pathogenic Variant Carriers Have an Increased Risk of Lung Cancer?
Authors: Vincent Fallet, Mateo Sanchis-Borja, Patrick R. Benusiglio, Jacques Cadranel
Journal: Journal of Clinical Oncology (2022)

Li et al 1 recently reported the association between risk of 22 cancers and BRCA1 and BRCA2 pathogenic variants (PVs) in the Consortium of Investigators of Modifiers of the BRCA1/2 cohort.Among 3,184 BRCA1 and 2,157 BRCA2 families, BRCA1 and BRCA2 PVs were associated with an increased risk of male breast, pancreatic, and stomach cancer; male BRCA2 PV carriers had also an increased prostate cancer risk.The authors did not observe increased risks for other cancers, lung cancer in particular.Indeed, overall lung cancer relative risk (RR) was 1.37 (95% CI, 0.85 to 2.21) and 1.13 (95% CI, 0.63 to 2.03) for BRCA1 and BRCA2, respectively.Nevertheless, it would be premature, in our opinion, to rule out an association between BRCA2 PV and lung cancer for the following reasons:
Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs
Authors: Anna Eisenstein, Brandon K. Hilliard, Scott D. Pope, Cuiling Zhang, Pranali Taskar, Daniel A. Waizman, Kavita Israni-Winger, Hui Tian, Harding H. Luan, Andrew Wang
Journal: Immunity (2022)
Femtosecond Laser-Assisted Cataract Surgery
Authors: Charles C. Lin, Jennifer R. Rose-Nussbaumer, Zaina N. Al-Mohtaseb, Seth M. Pantanelli, Walter Allan Steigleman, Kathryn M. Hatch, Marcony R. Santhiago, Stephen J. Kim, Julie M. Schallhorn
Journal: Ophthalmology (2022)
Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial
Authors: Boris Julg, Kathryn E. Stephenson, Kshitij Wagh, Sabrina C. Tan, Rebecca Zash, Stephen Walsh, Jessica Ansel, Diane Kanjilal, Joseph Nkolola, Victoria E. K. Walker-Sperling, Jasper Ophel, Katherine Yanosick, Erica N. Borducchi, Lori Maxfield, Peter Abbink, Lauren Peter, Nicole L. Yates, Martina S. Wesley, Tom Hassell, Huub C. Gelderblom, Allen deCamp, Bryan T. Mayer, Alicia Sato, Monica W. Gerber, Elena E. Giorgi, Lucio Gama, Richard A. Koup, John R. Mascola, Ana Monczor, Sofia Lupo, Charlotte-Paige Rolle, Roberto Arduino, Edwin DeJesus, Georgia D. Tomaras, Michael S. Seaman, Bette Korber, Dan H. Barouch
Journal: Nature Medicine (2022)

Abstract HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4 + T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg −1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg −1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log 10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml −1 . The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.
Monoclonal Autoantibody Against a Cryptic Epitope on Tissue-Adherent Low-Density Lipoprotein for Molecular Imaging in Atherosclerosis
Authors: Ramzi Y. Khamis, Adam Hartley, Mikhail Caga-Anan, Samata S. Pandey, Cinzia Marceddu, Chiari Kojima, Shang-Hung Chang, Joseph J. Boyle, Jason L. Johnson, Harry Björkbacka, Liang Guo, Aloke V. Finn, Renu Virmani, Jan Nilsson, Dorian O. Haskard
Journal: JACC. Cardiovascular imaging (2022)

Antibody-based constructs for molecular imaging and therapeutic delivery provide promising opportunities for the diagnosis and treatment of atherosclerosis.The authors aimed to generate and characterize immunoglobulin (Ig)G monoclonal autoantibodies in atherosclerosis for targeting of novel molecular determinants.The authors created hybridomas from an unimmunized low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mouse and selected an IgG2b isotype autoantibody, LO9, for further characterization.LO9 reacted well with native LDL bound to immobilized matrix components and less well to oxidized LDL. LO9 binding to immobilized native LDL was not neutralized by fluid-phase native LDL, indicating an adhesion-dependent epitope. The authors localized the epitope to a 20 amino-acid peptide sequence (P5) in the globular amino-terminus of apolipoprotein B. LO9 reacted with antigen in mouse atherosclerosis and in both human stable and ruptured coronary atherosclerosis. Furthermore, in vivo near-infrared fluorescence molecular tomographic imaging, and ex vivo confocal microscopy showed that intravenously injected LO9 localized beneath endothelium of the aortic arch in Ldlr-/- mice, in the vicinity of macrophages.The authors believe LO9 is the first example of an IgG autoantibody that reacts with a native LDL epitope revealed by adherence to tissue matrix. Antibodies against adherent native LDL have potential as molecular targeting agents for imaging of and therapeutic delivery to atherosclerosis.
Rapid molecular diagnostics of tuberculosis resistance by targeted stool sequencing
Authors: Doctor B. Sibandze, Alexander Kay, Viola Dreyer, Welile Sikhondze, Qiniso Dlamini, Andrew DiNardo, Godwin Mtetwa, Bhekumusa Lukhele, Debrah Vambe, Christoph Lange, Muyalo Glenn Dlamini, Tara Ness, Rojelio Mejia, Barbara Kalsdorf, Jan Heyckendorf, Martin Kuhns, Florian P. Maurer, Sindisiwe Dlamini, Gugu Maphalala, Stefan Niemann, Anna Mandalakas
Journal: Genome Medicine (2022)

Stool is an important diagnostic specimen for tuberculosis in populations who struggle to provide sputum, such as children or people living with HIV. However, the culture of Mycobacterium tuberculosis (M. tuberculosis) complex strains from stool perform poorly. This limits the opportunity for phenotypic drug resistance testing with this specimen. Therefore, reliable molecular methods are urgently needed for comprehensive drug resistance testing on stool specimens.
Refining colorectal cancer classification and clinical stratification through a single-cell atlas
Authors: Ateeq M. Khaliq, Cihat Erdogan, Zeyneb Kurt, Sultan Sevgi Turgut, Miles W. Grunvald, Tim Rand, Sonal Khare, Jeffrey A. Borgia, Dana M. Hayden, Sam G. Pappas, Henry R. Govekar, Audrey E. Kam, Jochen Reiser, Kiran Turaga, Milan Radovich, Yong Zang, Yingjie Qiu, Yunlong Liu, Melissa L. Fishel, Anita Turk, Vineet Gupta, Ram Al-Sabti, Janakiraman Subramanian, Timothy M. Kuzel, Anguraj Sadanandam, Levi Waldron, Arif Hussain, Mohammad Saleem, Bassel El-Rayes, Ameen A. Salahudeen, Ashiq Masood
Journal: Genome biology (2022)

Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells.Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance.Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.